The phenomenon of multidrug resistance (MDR) was demonstrated at the end of the 1970s on cancer cell lines rendered resistant to chemotherapeutic drugs, in particular drugs used for the treatment of cancers. Multidrug resistance is characterized by a pleiotropic resistance, with respect to chemotherapeutic drugs used for the treatment of a patient, when these drugs have different structures and specificities. Among the drugs capable of selecting or inducing pleiotropic resistance of the cancer cell, mention will be made of colchicine, adriamycin, actinomycin, vincristine, vinblastine and mitoxantrone. From a phenotypic point of view, multidrug resistance is characterized by a decrease in the intracellular accumulation of cytotoxic drugs, physiological modifications of the cell and overexpression in the cell membrane of P-glycoprotein, also called P-gp protein or alternatively P-170 protein (Van der Bliek et al. 1988. Gene 71(2): 401-411, Thiebaut et al. 1987 Proc. Natl. Acad. Sci. 84(21): 7735-7738, Endicott et al. 1989 Annu. Rev. Biochem. 58: 137-171). The P-170 protein is responsible for an active flux of medicaments out of the cell (also called active efflux), this phenomenon being dependant on ATP consumption. The recognition by the P-170 protein, and the P-170 protein-mediated excretion out of the treated cell, of a large variety of chemical compounds having diverse structures and functions remains one of the most enigmatic aspects of the function of this protein. The lack of demonstration of a common structural characteristic between the drugs which are the subject of cross resistance does not allow the development of drugs which would not be excreted, under the influence of P-170 protein, to be envisioned.
Multidrug resistance of tumors to chemotherapy agents constitutes a central problem in medical cancerology. While progress in support treatments are observed, the problem of drug resistance remains an obstacle to obtaining better cure rates. It is noted that the tumor cells may not respond to chemotherapy from the beginning of treatment. This de novo multidrug resistance is unfortunately common in several types of solid tumors. Moreover, it has been possible to observe a phenomenon of acquired resistance, which manifests itself in tumors which, at the beginning, responded to chemotherapy and which subsequently developed, in the more or less short term, resistance to treatments.
In order to be more effective, anticancer treatments have been combined with multidrug resistance-modulating agents, also called reverting agents, which can block the P-170 protein-mediated outflux of drugs out of the cell and thus circumvent multidrug resistance. The existing reverting agents, such as verapamil, quinine and cyclosporin, result in toxicity that is unacceptable for the patient when they are used at the doses required to inhibit the efflux activity of the P-170 protein. For example, verapamil rapidly showed its limits in the treatment of cancer reversion due to the appearance in the patient of dysfunctions such as hypotension, cardiac arrhythmia and congestive heart failure when it was administered at the curative dosage, which are also the limiting doses for toxicity (Miller et al. 1991. J Clin Oncol 9(1): 17-24).
More recent analogues, such as dexverapamil, PSC 833 (cyclosporin derivative) and, most recently, S9788 from Laboratoires Servier, have been the subject of clinical trials, the aim of which was to overcome multidrug resistance. However, these novel reverting agents experience limits for use that are comparable to those reported for the prior generation of reverting agents. In fact, the trials for treatment of multidrug resistance using S9788 (6-[4-[2,2-di-(4-fluorophenyl)ethylamino]-1-piperidinyl]-N,N′-di-2-propenyl-1,3,5-triazine-2,4-diamine), a triazineamino-piperidine derivative, have characterized the limits for use of this product, subsequent to the appearance of phenomena of cardiac toxicity, ventricular arrhythmia and torsade de pointe (Stupp et al. 1998. Ann Oncol 9(11): 1233-1242). Consequently, the multidrug resistance phenomenon is difficult to hold back with reverting agents, novel and conventional, due to treatment doses equivalent to the thresholds of toxicity for the patient who has become refractory to the chemotherapy.
Immunotherapy, in particular the use of monoclonal antibodies, has also been envisioned for treating multidrug resistance appearing in the patient. It was tested first for inhibiting the formation of tumors in ovarian cancer using the monoclonal antibody MRK16 (Tsuruo. 1989. Cancer Treat Res 48: 1811-1816). More recently, monoclonal immunotherapy in the treatment of multidrug resistance has been investigated more thoroughly by Mechetner and Roninson (1992. Proc Natl Acad Sci USA vol. 89 pp. 5824-5828). In fact, monoclonal antibodies UIC2 directed against an extracellular epitope of human P-glycoprotein were obtained and tested in vitro on cell lines resistant to anticancer agents. It was then shown that the inhibitory effect, in vitro, of the monoclonal antibodies UIC2 is comparable to that of verapamil used as maximum clinical doses (3 μM). The anti-P-170 monoclonal antibodies exert their effect by inhibiting the ATPase activity of the P-170 protein and by inhibiting the binding of medicinal products to the P-170 protein.
An appropriate immunotherapy, based on the injection of monoclonal antibodies into a patient, can have certain advantages insofar as it can eliminate the residual resistant cells of a tumor. However, the lack of knowledge of the specificity, of the toxicity, of the efficacy and of the mechanism of action of the antibodies limits the use of this approach for overcoming multidrug resistances due to the overexpression of the P-170 protein. In particular, the side effects related to the anti-mouse antibodies or anti-rabbit antibody immune reactions and the difficulties related to the lack of humanization of the monoclonal antibodies are not mastered in monoclonal immunotherapy.